DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant's election with traverse of:
(i) 12 mg/kg/hour (amended independent claim 45 is now limited to this dosing rate in line 7)); and
(ii-a) a combination of the besylate salt of methyl [3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate and remifentanil (amended independent claim 45 is now limited to this combination);
in the reply filed on 12/20/2023 remains acknowledged.
Claim 48 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected specie, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/20/2023.
Response to Arguments
Applicants' arguments, filed 8/6/2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Applicant’s arguments, see p. 4, filed 8/6/2025, with respect to the rejection under 35 USC 112(a) have been fully considered and are persuasive, in view of the claim amendments. The rejection of claims 45, 53-55 has been withdrawn.
Applicant's arguments regarding the obviousness rejection have been fully considered but they are not persuasive.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 45, 53-55 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Antonik et al. (“A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics”; 2012 Aug; Anesth. Analg.;115(2): 274-83; doi: 10.1213/ANE.0b013e31823f0c28; IDS 12/13/2023 reference); in view of Wiltshire et al. (“A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation”; 2012 Aug; Anesth Analg.;115(2): 284-96; doi: 10.1213/ANE.0b013e318241f68a; IDS 12/13/2023 reference); Wilhelm-Ogunbiyi et al. (EP 2 450 039 A1; 2012 May; IDS 12/13/2023 reference); Bard (“The BIS monitor” A Review and Technology Assessment”; 2001; AANA Journal; 69(6): 477-483; cited in a prior Office action); and Rogers et al. (“Remimazolam, a short-acting GABAA receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures”; 2010; IDrugs; 13(12): 929-937; IDS 12/13/2023 reference), as evidenced by Sneyd (“Remimazolam: New Beginnings or Just a Me-Too?”; 2012 Aug; Anesth. Analg.;115(2): 274-83; doi: 10.1213/ANE.0b013e31823acb95; IDS 12/13/2023 reference).
Claim 56 has been canceled.
According to the PubMed record of Antonik (PMID: 22190555; http://www.ncbi.nlm.nih.gov/pubmed/22190555, accessed 6/9/2016; cited in prosecution of the parent application), Antonik was electronically published 2011 Dec 20.
Antonik teaches (abstract):
BACKGROUND: A new benzodiazepine, remimazolam, metabolized by tissue esterases to an inactive compound, CNS 7054, has been developed to permit a fast onset, a short and more predictable duration of sedative action, and a more rapid recovery profile than with currently available benzodiazepines. We report on the safety and efficacy of the first human study.
METHODS: A phase I, single-center, double-blind, placebo- and active-controlled, randomized, single-dose escalation study was conducted. Up to 10 cohorts of healthy subjects were scheduled to receive a single 1-minute IV infusion of remimazolam, midazolam, or placebo. In the 10 possible cohorts, remimazolam doses were from 0.01 to 0.35 mg/kg. In cohorts 1 to 3, 6 subjects received remimazolam and 1 placebo. From cohort 4 onward, an additional 3 subjects in each cohort received midazolam (0.075 mg/kg). Safety, pharmacokinetics, and pharmacodynamics were measured. A stop criterion of loss of consciousness for >5 minutes in >50% of subjects was predefined.
RESULTS: The stop criterion was reached in cohort 9 (0.30 mg/kg remimazolam) so that 81 subjects were enrolled. Remimazolam was well tolerated in all dose cohorts, and no serious adverse events (AEs) were reported. Three AEs of mild (Spo(2) 85%-88%) hemoglobin desaturation (2 in the remimazolam groups and 1 in the midazolam group) resolved spontaneously, and 1 AE of moderate hemoglobin desaturation (Spo(2) 75%) resolved with a chin lift in the highest remimazolam dose group. No supplemental oxygen or manual ventilation was required. Vital signs remained stable throughout, although there was an increase in heart rate 2 minutes postdose for both remimazolam and midazolam. There were no reports of hypo- or hypertension. The pharmacokinetic behavior of remimazolam was linear and its systemic clearance approximately 3 times that of midazolam. Clearance was essentially independent of body weight. A rapid onset and dose-dependent sedation was observed after administration of remimazolam at 0.05 mg/kg and higher. Remimazolam (0.075 to 0.20 mg/kg) induced peak sedation levels similar to or higher than those achieved with midazolam (0.075 mg/kg). Median recovery times after approximately equieffective doses of remimazolam (0.10 and 0.15 mg/kg) and midazolam (0.075 mg/kg) were 10 and 40 minutes, respectively.
CONCLUSIONS: Remimazolam provided sedation with rapid onset and offset, and was well tolerated. There was no supplemental oxygen or ventilation required. On the basis of these data, further studies on the potential utility of remimazolam for sedation/anesthesia are warranted.
Intravenous dosing over 1 minute of 0.05-0.3 mg/kg corresponds to an intravenous hourly rate of 3-18 mg/hour/kg, a rate within the range of claim 72 (a), and encompassing the range of new claim 92 (a), rendering it obvious (MPEP 2144.05 (I): In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)). The 0.3 mg/kg dose (18 mg/hour/kg) achieved loss of consciousness for >5 minutes in >50% of subjects (anesthesia). In considering Figure 4, for the 0.2 mg/kg dose (i.e., Applicant elected 12 mg/hour/kg, encompassed by each of claims 72(a) and 92(a)), the patients achieved loss of consciousness (MOAA/S scores of < 2; see p. 278, 1st paragraph) in less than 6 minutes.
Antonik teaches the BP was stable, with 4 reports of changes (1 low systolic BP at 8 hours postdose, and 3 elevations) that were considered to be mild and unrelated to the study medication (p. 280, column bridging paragraph). One individual with low systolic BP (hypotension) out of 54 individuals administered remimazolam (see Table 5), corresponds to an incidence rate of 2%, i.e., less than 15%.
Antonik specifically suggests, as a result of the study conducted, that on the basis of these data, further studies on the potential utility of remimazolam, including for anesthesia, are warranted (abstract; Conclusions). Thus, Antonik demonstrates the suitability of remimazolam for Applicant elected anesthesia. Antonik further teaches the patient population, Subjects eligible to take part in this study were healthy males or females, ages 18 to 55 years inclusive (p. 275, Subjects; this age range substantially overlaps with the elected age range, 20-65, rendering obvious the claimed patient range).
Antonik does not teach Applicant elected 2 step process, which includes both inducing and maintaining anesthesia, required by claim 92, and claims dependent therefrom, where the dose of the second step corresponds to the elected 1 mg/hour/kg, nor continuous intravenous administration during steps (a) & (b), required by independent claim 92.
Antonik does not teach the besylate salt of remimazolam, or the required combination with remifentanil
Wiltshire teaches (abstract):
BACKGROUND: A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study.
METHODS: A phase I, single-center, double-blind, placebo and active controlled, randomized, single-dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01–0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens.
RESULTS: A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer’s Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index–IC50: 0.26, 0.07 µg/mL; γ: 1.6, 8.6; ke0: 0.14, 0.053 min-1 ; IMAX: 39, 19, and MOAA/S–IC50: 0.4, 0.08 µg/mL; γ: 1.4, 3.4; ke0: 0.25, 0.050 min-1 for remimazolam and midazolam, respectively. Simulations to obtain 70% of the population with MOAA/S scores of 2 to 4 were developed. This criterion was achieved (95% confidence intervals: 67%–74%) with a 6-mg initial loading dose of remimazolam followed by 3-mg maintenance doses at 2-minute intervals. Recovery to a MOAA/S score of 5 is predicted to be within 16 minutes for 89% (95% confidence intervals: 87%–91%) of the treated population after this loading/maintenance dose regimen.
CONCLUSIONS: Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than with slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65–90 kg).
Wiltshire models the observed bispectral index scores (see Figure 6), indicating the usefulness of BIS monitoring of sedation.
Figure 7 shows a 9 mg dose, which achieved MOAA/S score of 0 within 2 minutes of the dose. Assuming a typical 70kg adult, this 9 mg dose, administered over 1 minute, corresponds to 8 mg/hour/kg dose, which was effective for an initial induction of anesthesia for this patient. This dose is within the range of 0.01-0.3 mg/kg taught, administered over 1 minute (range corresponds to 0.6-18 mg/hour/kg). Figure 7 also shows the patient leaving Zero MOAA/S score within 5 minutes, and full recovery to MOAA/S score of 5 within 15 minutes. Thus, the skilled artisan would recognize that maintaining anesthesia after the initial anesthesia is achieved would require maintenance dosing of remimazolam.
The Monte-Carlo simulations of Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scores during and after a 6-mg initial loading dose of remimazolam followed by up to four 3-mg maintenance doses (model Rem-R13-MOA02). Maintenance doses were given no closer than 2 minutes after the previous dose. They were introduced if the MOAA/S score reached 4 during the 18-minute duration of the “procedure.” If the initial loading dose did not reduce the score below 3, the first maintenance dose was given at that score. “‰” frequency per thousand subjects (Figure 14). The optimal regimen, in terms of minimizing the numbers of dropouts, failures, and subjects with MOAA/S scores of zero, seemed to be a 6-mg initial loading dose followed by 3-mg maintenance doses. This delivered sedation with MOAA/S scores between 2 and 4 to at least 70% of the subjects from 2 minutes after the end of the loading dose until the end of the 18-minute procedure (Fig. 12). Estimates of percentage of subjects suitably sedated ranged from 70.5%, 3 minutes after the start of the infusion (95% confidence intervals: 67%–74%), to 90% (95% confidence intervals: 92%–94%) between 4 and 8 minutes later (p. 293, 1st paragraph). Thus, the objective of this Monte Carlo was to achieve sedation, but without loss of consciousness for most patients. The bottom two lines of Figure 9 demonstrate that about 7% of these patients achieved loss of consciousness (MOAA/S scores of 0; i.e., anesthesia) for about 20 minutes.
Assuming a 70 kg adult, the 6 mg initial loading dose, dosed over 1 minute, corresponds to dosing 5 mg/hour/kg (within about 6 mg/hour/kg). The subsequent four 3 mg maintenance doses, dosed over 18 minutes, correspond to 12 mg/70 kg/18 minutes x 60 minutes/hour, or about 0.57 mg/hour/kg (or, if dosing were limited to 12 minutes, 0.86 mg/hour/kg), within about 1 mg/hour/kg, maintenance dose. Because the objective of this Monte Carlo simulation was achieving sedation, not loss of consciousness in most patients, it is clear that both the initial and the subsequent maintenance dose levels of remimazolam administration would have to be increased, in order to achieve loss of consciousness / anesthesia in most patients. Thus, the teachings of Antonik together with Wiltshire provide motivation for a two-step dosing regimen, starting with higher anesthesia induction dosing, followed by maintenance dosing, to maintain stable anesthesia. Determination of specific mg/hour/kg amounts in each step, for instance, as required by instant claims 45, 47, would have been obvious as a result of routine optimization, in order to induce and maintain loss of consciousness.
The teachings of Antonik and Wiltshire are set forth above, and how they render obvious Applicant elected two-step method of inducing and maintaining analgesia.
Antonik does not teach the benzenesulfonate (besylate) salt of remimazolam, required by claim 45 and claims dependent therefrom. Antonik does not teach Applicant elected combination of remimazolam + remifentanil, as required by claim 45.
Wilhelm-Ogunbiyi teaches dosing regimen for sedation with CNS 7056 (Remimazolam) (title), which corresponds to 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl] propionic methyl ester. A dosing regimen for sedation with the fast-acting benzodiazepine CNS 7056 in combination with an opioid, in particular fentanyl, whereas CNS 7056 is given in a dose of 2 to 10 mg, preferably between 4 and 9 mg and most preferably between 5 and 8 mg (abstract). Sedation represents a hallmark of modern medicine and is widely used with its application ranging from minor surgery or diagnostic procedures up to ventilation of patients in intensive care units. Several classes of sedatives are known; among them benzodiazepines, which are often used and administered in combination with opioids. This combination represents the current gold standard for sedation [0002]. Because of this variable response, the generally recommended procedure for a clinician attempting to achieve optimal sedation is to administer an initial bolus and then titrate the drug to the patient by incremental dosing until the desired level of sedation is achieved. The resulting dosing regimen which defines the initial and subsequent top-up doses and the time interval between the doses has to consider the drug's particular pharmacokinetic and pharmacodynamics properties, and has to be specifically adopted to the utilized sedative compound. Finally, the route of administration has to be defined (e.g. intravenous, oral, rectal, intramuscular, etc.) [0004]. The compound 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiaze-pin-4-yl] propionic methyl ester (hereinafter "CNS 7056") represents one of these ultra-short-acting benzodiazepines (disclosed as example 35 lc-8 of EP 1 183 243 81 ). CNS7056 was tested in clinical Phase I and Phase II studies with and without combination with fentanyl for producing sedation for endoscopy or colonoscopy, wherein CNS 7056 was given as body-weight adjusted dose. In these studies (CNS 7056-001, CNS 7056-002 and CNS 7056-003) CNS 7056 exhibited a fast-onset, short duration of action and rapid recovery profile.
[0014] It is thus the objective of the present invention to provide a convenient and safe dosing regimen for the ultrashort-acting benzodiazepine CNS 7056 which also results in an improved sedation profile.
[0015] This objective is solved by the use of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidozo[1,2-a][1,4]benzodiazepin-4-yl] propionic methyl ester (CNS 7056), according to formula (I) or pharmaceutically acceptable salt or solvate thereof for the induction and/or maintenance of sedation, whereby CNS 7056 is administered in combination with an opioid according to claim 1.
[0018] The term "sedation" refers to a relaxed, calm state of the body and mind which is induced pharmacologically, e.g. by the use of sedatives. … Furthermore, as defined herein, the term sedation includes also deep sedation, preoperative sedation, … conscious sedation during short diagnostic, operative or endoscopic procedures, and sedation prior and/or concomitant to the administration of other anaesthetic or analgesic agents.
[0038] … As a synonymous term for “operative procedure” the term “surgery” is also used herein.
In a most preferred aspect of the invention the patient is given a fentanyl analogue selected from a group including remifentanil [0068] (claim 7).
The dosing schemes include as high as 10 mg (claim 1). When 10 mg is dosed to a 70 kg adult, over 1 minute the dosing rate corresponds to 9 mg/hour/kg. Up to 6 top-up doses are taught, with 2-5 minutes between, in preferred amounts of 2-3 mg (claims 2, 4-5). 3 mg top up doses, 4 times, with 5 minutes between, corresponds to 12 mg dosed over 20 minutes. When administered to a 70 kg adult, this maintenance dosing corresponds to 0.51 mg/hour/kg. As shown in Table 15, the highest 9 mg doses with 3-4.5 mg top-ups, where 3-4 top up doses were administered, achieved a 0 MOAA/S score in 5-13% of the patients. The skilled artisan would have recognized that higher doses would be more effective for anesthesia in a larger number of patients.
Table 18 shows dosing regimens for a combination of remimozalam (CNS 7056) + fentanyl, which include:
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6 mg remimazolam initial dose in a 70 kg patient, administered over 1 minute corresponds to 5.1 mg/hour/kg. The 4 mg top up doses, with 4 top-ups, and a 4 minute dosing gap (see Table 17) (16 minutes) administered to a 70 kg patient corresponds to a dosing rate of 0.85 mg/hour/kg. With fentanyl, the Zero MOAA/S scores (loss of consciousness) were in the range from 10-12%. The skilled artisan would have been motivated to increase the initial and maintenance doses, to achieve a higher % of anesthesia.
Example 2 [0124] ff discusses a Phase IIb study of remimaozalm [sic] vs. midazolam in using combination fixed doses. Four dose schemes are set forth [0126]:
The patients received one of the following doses of Midazolam or Remimazolam:
• Midazolam 2.5 mg with 1.0 mg top-ups (40 patients)
• Remimazolam - 8.0 mg with 3.0 mg top-ups (40 patients)
• Remimazolam - 7.0 mg with 2.0 mg top-ups (40 patients)
• Remimazolam 5.0 mg with 3.0 mg top-ups (40 patients)
It is stated [0127]: The doses of Remimazolam were selected based on the findings of the three previous clinical trials as predicted by the comprehensive PK/PD analysis
(see Example 1).
Example 1 describes a pharmacokinetic study labeled Study CNS 7056-001,
[0096] Pharmacokinetic data were obtained after CNS 7056 had been administered by intravenous infusion over one minute to groups of healthy volunteers at the following doses: 0.01, 0.025, 0.05, 0.075, 0.1, 0.15, 0.2, 0.25 and 0.3 mg/kg. Both arterial (1, 2, 3, 4, 6, 8, 10, 12, 15, 20, 30, 45 minutes and 1, 2, 3, 4 hours post-dose) and venous (2, 3, 4, 6, 8, 12 hours) blood samples containing CNS 7056 and its metabolite, CNS 7054, were obtained from indwelling catheters. Concentrations of CNS 7056 and CNS 7054 were measured using HPLC with tandem mass spectrometric detection. Measurements of sedation (MOAA/S and Bispectral Index (BIS) scores) and systolic and diastolic blood pressure were made at regular intervals.
A second study, CNS 7056-002 involved fentanyl and then loading doses of CNS 7056,
[0097] In the second part of the study, all subjects received a 50 mcg intravenous dose of fentanyl followed by a further 25 mcg if the initial pain relief was inadequate. Three cohorts of 15 patients were given loading doses of CNS 7056 at 5 0.04, 0.075 or 0.1 mg/kg with the higher doses only being administered once the safety of the lower doses had been assessed. Up to a maximum of two supplemental, 0.04 mg/kg doses of CNS 7056 were administered, not less than two minutes apart to obtain adequate sedation (MOAA/S ~ 3) for insertion of the colonoscope. Further 0.04 mg/kg doses of CNS 7056 were administered during the procedure, no earlier than two minutes after the previous dose, in order to maintain a MOAA/S level of~ 4 for 30 minutes; no more than seven doses (the initial and six top-up doses) could be 10 administered to any subject. The gender ratio in each cohort was 7 : 8. Venous plasma levels of CNS 7056 were measured at 1, 5, 10, 20 and 30 minutes and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose.
Fitting the combined data obtained from studies CNS 7056-001 and CNS 7056-002 to 3- and 4-compartment pharmacokinetic models is discussed at [0098]. Preferred models gave derived pharmacokinetic parameters, which were then used to simulate the arterial concentrations at time points at which pharmacodynamic data, MOAA/S scores and blood pressures, were obtained and sigmoid inhibitory pharmacodynamics models were fitted to the observations. Sudden, random, increases in MOAA/S score were identified, and attributed to external stimuli such as acute pain from the colonoscope or treatment by nursing staff; these were modeled by introduction of a covariate which increased ED50, and another covariate, the “scoping factor” which was added to the model in order to simulate reduced sedation during the actual colonoscopy procedure caused by general irritation [0098].
At the discussion of the PK-PD analysis [0099], it is noted that
Clearance of CNS 7056 to CNS 7054 was assumed to take place from the central, pulmonary or peripheral compartments, or from a hepatic one (Figure 2). A combination of two clearance compartments was also investigated. An additional "deeper" compartment was introduced as models with four-compartments had been shown to be superior to those with three in study CNS 7056-001.
[Examiner note: it appears that the “deeper” compartment corresponds to Vs discussed by Krejcie.]
Thus, Wilhelm-Ogunbiyi establishes that remimazolam has advanced to Phase IIb clinical trials, being effective in a sedation dosing regimen involving an initial bolus dose, followed by a series of top-up doses, which maintain sedation; i.e., a two-phase regimen, involving different dosing levels for each phase. Wilhelm-Ogunbiyi discusses surgical procedures as one application of sedation, rendering obvious the application of this two-phase dosing regimen to surgery. This regimen has been established based on PK-PD data from the models discussed.
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to modify the teachings of Antonik, by substituting the benzenesulfonate salt of remimazolam, to achieve the desired anaesthesia by a two-step dosing administration process, achieving anesthesia at a higher dose, and maintaining anesthesia at a lower dosing. The motivation to use the benzenesulfonate salt of remimazolam would have been the expectation that this salt would also achieve the anesthesia which is taught by these references, and because this salt is preferred by Wilhelm-Ogunbiyi. Dosing via continuous infusion would have been obvious as an alternative to repeated bolus doses, i.e., of the type taught by Wilhelm-Ogunbiyi, as evidenced by the discussion of Sneyd of alternatives that should be studied.
It would further have been obvious to combine the remimazolam benzenesulfonate (i.e., besylate) salt with Applicant elected remifentanil, taught by Wilhelm-Ogunbiyi. The motivation would have been to achieve more effective analgesia, at lower dosing.
Regarding the elected 12 mg/kg/hour inducing dose, the Examiner notes that the highest dose taught by Antonik, which achieves 50% anesthesia for at least 5 minutes, dosed over 1 minute, corresponds to 18 mg/kg/hour. This is similar to 12 mg/kg/hour as recited. However, considering Wilhelm-Ogunbiyi teaches a synergy, i.e., lower dosing achieves sedation and analgesia, use of 12 mg/hour/kg, when combined with the elected remifentanil is construed as obvious as a result of routine optimization.
Regarding the elected maintenance dose of 1 mg/kg/hour, the top off dosing taught by Wilhelm-Ogunbiyi the 4 mg top up doses, with 4 top-ups, and a 4 minute dosing gap (see Table 17) (16 minutes) administered to a 70 kg patient corresponds to a dosing rate of 0.85 mg/hour/kg. Using a 3 minute dosing gap (see Table 17), the dose rate corresponds to 1.1 mg/hour/kg. Thus, the elected dose rate of 1 mg/kg/hour is within the range of maintenance taught, and would have been obvious as a result of routine optimization, to maintain blood levels of remimazolam besylate high enough to maintain anesthesia, when administered together with remifentanil. Final administered dosing rates are construed as obvious as a result of routine optimization, for the purpose of achieving anesthesia.
Regarding the BIS score range, Antonik also reports bispectral index (BIS) data scores (see Figure 5). These values reach about 60 (Remimazolam 0.15 mg/kg and 0.30 mg/kg). However, Antonik does not teach surgical BIS scores between 40-52 (construed as continuously scoring in this range for the duration of surgery) as required by independent claim 45. Nonetheless, targeting such BIS scores is well known to measure anesthetic state.
Bard teaches the incidence of recall and awareness under general anesthesia has been reported to be between 0.2% and 1.6%, but is likely underreported. Bard discusses a quote demonstrating that the patient can have devastating psychological and cognitive effects (p. 477, 2nd paragraph).
The BIS [bispectral index] monitor is, to date, the most effective and the only US Food and Drug Administration-approved monitor to measure the anesthetic state of the central nervous system. This article reviews the development of the technology of the BIS monitor (p. 477, 3rd paragraph).
Figure 2 presents bispectral index (BIS) range guidelines. The range between 40 and 60 corresponds to general anesthesia, having a low probability of consciousness (p. 479). Potential benefits from the routine use of the BIS monitor include decreased risk of awareness, improved titration of anesthetic agents and decreased recovery room time. The BIS also gives the anesthetist additional information to consider when selecting drugs for interventions. (p. 479, 3rd paragraph). The BIS monitor is used by approximately 650 hospitals nationwide and has been used to monitor more than 1 million anesthetics. There have been 34 cases of confirmed awareness, where in 15 the BIS was more than 65 at the time of the awareness (p. 481, 3rd paragraph). Bard establishes BIS monitoring is frequently used for general anesthesia monitoring, and target BIS ranges from 40-60, with an exemplary score of 51 (Figure 6). Using the lower portion of the anesthesia range, 40-52 would have been obvious as a subset of the range taught, and a desire to rely on lower scores than the top end, moving further away from the 65 indicated to be associated with awareness in a few cases where BIS was utilized.
Thus, it would have been obvious, when applying the obvious method of inducing and maintaining general anesthesia during surgery with remimazolam, to monitor with BIS and to titrate continuous intravenous infusion with remimazolam to achieve and maintain the BIS range from 40-52, a subset of the anesthesia BIS score range taught by Berg (this is construed as obvious from within the range taught, per MPEP 2144.05 (I): In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)). The motivation to titrate and optimize continuous intravenous dosing by utilizing BIS scores within the claim 45 range would have been the benefits discussed by Bard, decreased risk of awareness, improved titration of anesthetic agents and decreased recovery room time, with the recognition BIS is FDA approved as a monitor for anesthetic state.
Maintaining anesthesia while monitoring BIS scores would have been expected to provide feedback about the level of anesthesia without incidence of recall/awareness, or the need for salvage treatment, until surgery was complete and it was desired to awaken the patient. This is the point of the BIS system as discussed by Bard. Adjustment of dose level during the maintenance phase, to maintain BIS scores, would have had the benefit of eliminating the incidence of recall and awareness under general anesthesia and the potential devastating psychological and cognitive effects taught by Bard. Thus, a method without salvage treatment would have been an obvious goal, achievable by monitoring BIS scores, and adjusting remimazolam doses to maintain the desired 40-52 BIS range, at least in most patients.
Sneyd is relied on as evidentiary of the instant obviousness rejection. Sneyd teaches this edition of the Journal includes 2 studies describing the first human administration of remimazolam, a novel benzodiazepine (citation is made to Antonik and Wiltshire; p. 217, first paragraph). In the present study, infusions were limited to 1 minute so we now need to see studies including repeat bolus doses and continuous infusion (p. 218, 2nd paragraph). During the development of midazolam, attempts were made to use it as sole hypnotic, in combination with an opioid, for induction and maintenance of anesthesia with attempts to reverse its effect after the end of surgery by administration of flumazenil. Remimazolam offers the opportunity to revisit this area, with and without flumazenil reversal, to evaluate whether hemodynamic stability, intense amnestic effects, or other benefits exist to make the process useful (p. 218, right, 2nd paragraph). Sneyd establishes that based on the 1 minute infusions of Antonik, the skilled artisan would have been motivated to utilize repeat bolus doses or, alternately, continuous infusion, with a reasonable expectation to achieve similar outcomes; thus, the skilled artisan would have had a reasonable expectation of success in use of continuous infusion in place of repeat bolus dosing. Even Sneyd suggests schemes for induction and maintenance of anesthesia, by comparing results from Antonik with those of prior tests using midazolam, supporting the Examiner’s position that the instant method of achieving anesthesia by using a 2-phase, induction and maintenance dosing phases, are obvious.
The results of Antonik, together with the modeling study of Wiltshire, clearly suggest further use of remimazolam in anesthesia (construed as general anesthesia, see continuum of Figure 2 of Bard):
CONCLUSIONS: Remimazolam provided sedation with rapid onset and offset, and was well tolerated. There was no supplemental oxygen or ventilation required. On the basis of these data, further studies on the potential utility of remimazolam for sedation/anesthesia are warranted. (Antonik, abstract)
for remimazolam … complete anesthesia (MOAA/S scores of zero) was
induced in 14 of 30 subjects given the higher doses (0.1–0.3 mg/kg) … (Wiltshire, 295, 6th paragraph)
The relatively short pharmacokinetic half-time for remimazolam of 7 to 8 minutes compared with approximately 60 minutes for midazolam (Fig. 10) indicates that recovery from sedation or anesthesia will be much more rapid. (Wiltshire, 295, 8th paragraph)
Thus, each of Antonik and Wiltshire are studies of sedation with remimazolam (each published in a journal that is directed toward anesthesia (& analgesia) [the journal audience would have clearly recognized the benefits demonstrated in a sedation study provide a reasonable basis for the suggestion of using remimazolam for anesthesia], but the results lead to the suggestion of utility of remimazolam for anesthesia. The skilled artisan would have utilized the findings in the sedation studies and the modeling based on the sedation studies to select conditions for the obvious two phase induction and maintenance (e.g., iv dosing parameters would have been obvious based on considerations of the teachings of these references).
Regarding administration of remimazolam in Wiltshire, by the Examiner’s count administration of remimazolam is taught in at least 10 locations in the text of Wiltshire. The Examiner does not dispute that Wiltshire is focused on modeling the results for pharmacokinetic and phramcodynamic modeling (title); but to say Wiltshire does not teach administration of remimazolam is in error. Wiltshire marks reference to the “clinical conduct of the study” in the accompanying report (reference 2 is citation to Antonik). Thus, Antonik and Wiltshire are based on different aspects/considerations of the same clinical study.
Sneyd discusses combination with an opioid for induction and maintenance of anesthesia with attempts to reverse its effect after the end of surgery by administration of flumazenil, which did not prove useful in midazolam development, but is suggested to revisit this area, with and without flumazenil reversal in remimazolam anesthesia development (218, 7th paragraph).
Each of these references are construed as suggesting (providing motivation) extending study of remimazolam (and the besylate salt) from sedation to general anesthesia, and to utilize continuous infusion (short action of remimazolam is suggestive that continuous infusion will be needed; continuous infusion is explicitly discussed by Sneyd at, inter alia, 218, 2nd paragraph: “In the present study, infusions were limited to 1 minute so we now need to see studies including repeat bolus doses and continuous infusion”). Sneyd clearly contrasts the use of midazolam, using 1 or more bolus injections, with short acting drugs, which require [continuous] infusion (remimazolam is established by these references as short acting; thus, anesthesia using continuous infusion is clearly a suggestion that is motivated by these teachings)
Based on considerations of Wilhelm Ogunbiyi details for the induction phase leading to anesthesia in some of the patients, the rejection provides a basis for obviousness of selection for the obvious method of inducting and maintaining general anesthesia using claimed dosing rates. Furthermore, amount considerations would have provided a starting point for routine optimization, which, absent evidence to the contrary, would have given the claimed range as a result of optimization.
As pointed out in MPEP 2144.05 II, generally differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
The rejection has set forth a reasonable basis for obviousness, which is associated with a reasonable expectation of success. Antonik explicitly suggests entry into anesthesia trials. In agreement that there is a reasonable expectation for success, the Examiner points out (in the prosecution of the parent application) that Rogers reviews development of remimazolam by GlaxoSmithKline, TheraSci, CeNeS Pharmaceuticals, PAION and Ono Pharmaceutical (930, 2nd paragraph). In spite of some non-serious adverse events, Rogers goes on to mention that a phase I clinical trial to evaluate the induction and maintenance of anesthesia with remimazolam in Japanese volunteers was initiated by Ono Pharmaceutical in February 2010 (933, 5th paragraph). See further discussion during prosecution of the parent application. Rogers documents that Ono Pharmaceutical entered into a Phase 1 clinical trial studying induction and maintenance of anesthesia, explicitly mentioned in the prior art reference, when Antonik and Wiltshire, inter alia, were taken into account. Clearly, this would outweigh parent prosecution arguments alleging there is no reasonable expectation of success.
As discussed in MPEP 2144.08 (II)(A)(4)(e), obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
The studies in sedation, with safety, and suggestion to utilize remimazolam for anesthesia provides the requisite reasonable expectation of success. It was previously noted, that even if the rejection relied on obviousness to try (MPEP 2143(I)(E): The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103."KSR, 550 U.S. at 421, 82 USPQ2d at 1397). The prior art suggests utilizing remimazolam (including the besylate salt) for (general) anesthesia, general dosing parameters rendering amounts of the claims obvious to utilize (especially when administered in combination with remifentanil), by relying on a BIS scale (40-52 range emerging as obvious from within the range for general anesthesia taught), would alternately have rendered the claims obvious. This would alternatively have supported an obvious to try basis.
Regarding the dosing rates during induction and maintenance, and induction time periods of achieving bi spectral index values of 53 or less of claims 45, 53, 54, the general parameters are taught as discussed above. Recited times and dosing rates are also considered prima facie obvious as a result of routine optimization.
Regarding the period of maintaining BIS at recited levels, about 85 to about 380 minutes (construed as 42.5-760 minutes) and the claim 56 range (4 hours to 6 hours), the goal of anesthesia would have been for purposes, such as surgical procedures, for which such time periods would have been needed; thus, the length of maintaining general anesthesia is also considered prima facie obvious, for the purpose of achieving general anesthesia. Use of the BIS values 40-52 would have facilitated maintaining the general anesthesia for these time periods.
Regarding the less than 15% incidence rate of hypotension, recited by claim 55, Antonik explicitly teaches no incidence of hypotension was reported (abstract). Thus, the outcome of claim 55 is considered predicted by the rejection; alternatively, the outcome is also considered characteristic of the obvious 2-phase induction and maintenance of general anesthesia in a patient.
Applicant argues based on two declarations by Professor Dr. Jürgen Schüttler and Dr. Thomas Stoehr, VP, Non-Clinical Development at Paion AG, which identify the parent application No. 14/424,340, and were originally filed in that application.
As VP of the company that corresponds to Applicant, Dr. Stoehr is an interested party in the outcome of examination, and this declaration is given less weight, in view of this interest.
Both declarations were originally filed and evaluated in the parent application, but not found to overcome the similar obviousness rejection applied in that application.
The Examiner reviewed the Declaration of Dr. Stoehr (originally filed in 14/424,340 11/14/2019, and refiled in the current application on 2/14/2025), but does not find that the opinion is persuasive to outweigh the obviousness basis. The Examiner notes that Dr. Stoehr is the Vice President of Paion, the instant application Applicant. Accordingly, Dr. Stoehr is considered an interested party, and opinions of the declaration are given less weight than would be given to a disinterested expert. (Nonetheless, each of Dr. Stoehr’s points raised have been fully addressed, as if Dr. Stoehr had been an uninterested party.)
Perhaps the call for further anesthesia studies does not rise to the level of “demonstration” of suitability for anesthesia, but it does rise to the level of a suggestion to carry out anesthesia studies, with a reasonable expectation of success based on these suggestions, supporting the obviousness rationale. Because continuous iv is clearly needed for truly short acting drugs (see discussion of Sneyd), and both induction and maintenance phases are employed for sedation (Wiltshire) and anesthesia (Sneyd), the skilled artisan would have found it obvious to rely on work by these references to select suitable dosing for these two phases for the anesthesia studies. Even the suggested study, in a clinical trial, would have read on the instant claims.
Side effects known for midazolam are not indicative of the same side effects for remimazolam. In fact, the discussion of Antonik indicates that remimazolam was well tolerated.
Regarding the profile of adverse events, Sneyd indicates remimazolam outperformed midazolam:
How did remimazolam fare in this investigation?
Remimazolam produces rapid-onset dose-related sedation
that is qualitatively similar to that produced by midazolam
but of substantially shorter duration. The profile of adverse
events suggests that the new compound is relatively
“clean” and remimazolam seems (so far) to be a “typical”
benzodiazepine. How is this achieved? Remimazolam is
built on a typical benzodiazepine structure and binds to
benzodiazepine receptors with reversal by flumazenil.
Pharmacokinetic modeling reveals remimazolam to have a
higher clearance and smaller volume of distribution than
midazolam; these explain the rapid offset of drug effect
after short-term administration.
(217, 5th paragraph, emphasis added)
Midazolam has an active metabolite that contributes materially to sedative effects (i.e., it has slower offset, complicated by the activity of the metabolite (217, 2nd paragraph). In contrast, the principle metabolite of remimazolam has 300 times lower affinity (much lower contribution than for midazolam metabolite) (218, 2nd paragraph).
The suggestion and expectation of success when utilizing remimazolam for anesthesia are not outweighed by the failure of other drugs in anesthesia applications, especially in view of the better (faster action and faster offset) of remimazolam. The references motivate development of remimazolam for general anesthesia, rendering the instant claims obvious.
As discussed in MPEP 2144.08 (II)(A)(4)(e), obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
The study in sedation, with safety, and suggestion to utilize remimazolam for anesthesia provides the requisite reasonable expectation of success. However, it is noted, that even if the rejection relied on obviousness to try (MPEP 2143(I)(E): The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103."KSR, 550 U.S. at 421, 82 USPQ2d at 1397). The prior art suggests utilizing remimazolam for (general) anesthesia, general dosing parameters rendering amounts of the claims obvious to utilize, including via BIS scale, would alternately have rendered the claims obvious.
Regarding the respiratory depression side effects, these were known at the time of the effective filing date. For instance, see Rogers et al. (“Remimazolam, a short-acting GABAA receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures”; 2010; IDrugs; 13(12): 929-937). Rogers reviews development of remimazolam by GlaxoSmithKline, TheraSci, CeNeS Pharmaceuticals, PAION and Ono Pharmaceutical (930, 2nd paragraph). Studies in mice, rats and sheep and pigs are discussed for sedation (931-932, in vivo section), including comparative depth of loss of consciousness and deeper sedation achieved by remimazolam than by midazolam; remimazolam has faster onset and offset than midazolam (931-932, bridging paragraph).
In the toxicity section, no significant toxicities have been identified in preclinical studies. In sheep remimazolam reduced normalized ventilator frequency, with transient increases in arterial CO2 tension, with respiratory acidosis, and decreases in arterial oxygen tension, with transient hemoglobin desaturation. Maximum reduction was 5.6%. There was mild, transient hypotension, but pressures were >60 mmHg (932, 4th paragraph). Non dose related reductions of respiratory frequency was observed in the 0.5-12 mg/kg range for sheep, but not in 12 mg/kg, where it was thought that there is a compensatory mechanism (932, 5th paragraph). These issues are characterized within “generally safe with a low risk of toxicity” and “no significant toxicities” description (932, 3rd paragraph).
Even with these minor respiratory issues recognized in animal models, Rogers goes on to describe a whole series of Phase I and II studies, and one expected phase III study in 2011. Side effects are discussed for these clinical trials (934), where remimazolam was well tolerated in phase I, with the worst side effects being two cases of mild hypoxia (SpO2 = 88%) that resolved without intervention, and one case of moderate hypoxia (SpO2 = 75%) that resolved with a chin lift (934, 3rd paragraph). A few patients requiring supplemental oxygen or chin lift are discussed as falling